Angiogenesis, the fundamental process by which new blood vessels are formed, is essential to a variety of normal body activities (such as reproduction, development and wound repair). Although the process is not completely understood, it is believed to involve a complex interplay of molecules which both stimulate and inhibit the growth of endothelial cells, the primary cells of the capillary blood vessels. Under normal conditions, these molecules appear to maintain the microvasculature in a quiescent state (i.e., one of no capillary growth) for prolonged periods which may last for as long as weeks or in some cases, decades. When necessary, however, (such as during wound repair), these same cells undergo rapid proliferation and turnover within a 5 day period. (The Journal of Biological Chemistry, 267: 10931-10934 (1987), Science, 235: 442-447 (1987)).
Although angiogenesis is a highly regulated process under normal conditions, many diseases (characterized as “angiogenic diseases”) are driven by persistent unregulated angiogenesis. For example, ocular angiogenesis has been implicated as the most common cause of blindness and dominates approximately 20 eye diseases. In certain existing conditions such as arthritis, newly formed capillary blood vessels invade the joints and destroy cartilage. In diabetes, new capillaries formed in the retina invade the vitreous, bleed, and cause blindness. Growth and metastasis of solid tumors are also angiogenesis-dependent (Cancer Research, 46: 467-473 (1986), Journal of the National Cancer Institute, 82: 4-6 (1989).
Because the pivotal role played by angiogenesis in tumor formation, metastasis, other disease conditions such as arthritis, inflammation, macular degeneration of age, and diabetic retinopathy, agents which inhibit angiogenesis have been the subject of active current research for their clinical potential.
In Proc. Natl. Acad. Sci. USA, 94: 6099-6103 (1997) and Chemistry and Biology, 4(6): 461-471 (1997) it is reported that both AGM-1470 and ovalicin, a sequiterpene isolated from the fungus Pseudorotium ocalis have been found to covalently inactivate a common bifunctional protein, type 2-methionine aminopeptidase (MetAP2) and is concluded that MetAP2 plays a critical role in the proliferation of endothelial cells and may serve as a promising target for the development of new anti-angiogenic drugs. The literature has thus established a casual link between inhibition of MetAP2 and the resultant inhibition of endothelial cell proliferation and angiogenesis. There is a need for discovery of new agents which inhibit MetAP2 for their potential as new drugs in combating angiogenesis and disease conditions which depend upon angiogenesis for their development.